DESC:FIELD OF THE INVENTION

[001] The present invention relates to a pharmaceutical solution for oral administration comprising lenalidomide and pharmaceutically acceptable excipients and the process for preparation thereof. Lenalidomide is used for the treatment of various types of cancers like multiple myeloma (MM), multiple myeloma (MM) following autologous hematopoietic stem cell transplantation (auto-HSCT), myelodysplastic syndrome (MDS), mantle cell lymphoma (MCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL).

BACK GROUND OF THE INVENTION

[002] Lenalidomide a thalidomide analogue, is an immunomodulatory agent with angiogenic and antineoplastic properties. The chemical name of lenalidomide is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following structure

[003] Lenalidomide is marketed as a solid capsule dosage forms comprising 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 25 mg of lenalidomide.

[004] Although capsules are generally acceptable solid dosage forms for oral administration, the solid dosage forms impose restrictions on the pharmaceutical usage of lenalidomide. Some patient populations having difficulty, physical or psychological, in swallowing solid dosage forms. Chen et al., [Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide; Clin Pharmcokinet (2017) 56:139-152] discloses that for the patients who have difficulty in swallowing solid oral capsules, lenalidomide capsules were disintegrated in hot water to form a suspension without grinding or opening capsules, and administered through a tube. If a liquid solution dosage form were available, these patients could more easily take the required dose of an oral liquid solution preparation by means of naso-gastric tube.

[005] However, such liquid solution preparations of lenalidomide are neither available on the market, nor in the art. To manufacture a liquid solution preparation of lenalidomide presents a problem to the skilled person in the art, as lenalidomide has poor solubility in pharmaceutically acceptable solvents. Therefore, the present invention relates to a stable liquid solution composition of lenalidomide.

OBJECTS OF THE INVENTION

[006] It is an object of the present invention to provide a stable liquid solution composition of lenalidomide in sufficient high concentration. It is particularly desired to provide a stable liquid solution of lenalidomide in which the concentration of lenalidomide is high enough to correspond to the concentration of the regular lenalidomide capsules.

[007] Lenalidomide exists in different polymorphic forms, of which non-hygroscopic hemihydrate is the desired polymorph for the preparation of lenalidomide capsules. Song etal., [Improving the solubility of lenalidomide via cocrystals, Cryst. Growth Des. 2014, 14, 3069-3077] discloses that the desired hemihydrate polymorph of lenalidomide has low oral bioavailability (below 33%) due to its poor solubility in water. The presence of these polymorphic forms precludes the formulation of the lenalidomide as a solution. With the low intrinsic solubility of the molecule, a small amount of lenalidomide wound enter aqueous solution and then leave it, crystallizing in the less desirable polymorphic form. Hence, it is further object of the present invention is to provide a stable liquid solution composition of lenalidomide wherein crystallization of the lenalidomide will not occur.

SUMMARY OF THE INVENTION

[008] In one embodiment the present invention provides a stable pharmaceutical liquid solution for oral administration comprising lenalidomide and a pharmaceutically acceptable excipient.

[009] In another embodiment the present invention provides a stable pharmaceutical liquid solution for oral administration comprising at least 1 mg/mL of lenalidomide and a pharmaceutically acceptable excipient.

[010] In a further embodiment the present invention provides a stable pharmaceutical liquid solution for oral administration comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide and
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate.

[011] In another embodiment the present invention provides a stable pharmaceutical liquid solution for oral administration comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate; and
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD).

[012] In a still further embodiment the present invention provides a stable pharmaceutical liquid solution for oral administration comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate;
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD);
(d) at least one preservative;
(e) at least one antioxidant and
(f) purified water.

DETAILED DESCRIPTION OF THE INVENTION

[013] The present invention provides a stable pharmaceutical liquid solution comprising lenalidomide and a pharmaceutically acceptable excipient.

[014] In one embodiment the present invention provides a stable pharmaceutical liquid solution comprising at least 1 mg/mL of lenalidomide and a pharmaceutically acceptable excipient. In embodiments of the invention the pharmaceutical liquid solution of the present invention preferably comprises of about 1 mg/mL to about 30 mg/mL, more preferably of about 1.5 mg/mL to about 25 mg/mL of lenalidomide and most preferably of about 2 mg/mL, 2.5 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 7.5 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 17.5 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 22.5 mg/mL, 23 mg/mL, 24 mg/mL and 25 mg/mL of lenalidomide.

[015] The pharmaceutically acceptable excipients used in the present invention are selected from the group comprising of organic solvents, cyclodextrin derivatives, preservatives, antioxidants, flavors, pH adjusting agents, purified water or combinations thereof.

[016] The possibility of providing lenalidomide in the form of an oral solution can be considered as new and surprising achievement per se. It is particularly the determination of suitable organic solvent or its mixtures thereof which overcomes the technical problem of providing a lenalidomide solution of sufficient high concentration comprising of about 1 mg/mL to about 30 mg/mL of lenalidomide. The organic solvents used in the present invention are preferably selected from the group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate or mixtures thereof. The more preferable organic solvent mixture used in the present invention is propylene glycol and triacetin. The organic solvent mixture most preferably used in the present invention consists about 50 mg/mL to about 1000 mg/mL of propylene glycol and about 1 mg/mL to about 25 mg/mL of triacetin.

[017] In another embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide and
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate.

[018] In a further embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide and
(b) an organic solvent mixture of propylene glycol and triacetin.

[019] In a still further embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide and
(b) an organic solvent mixture consisting of
(i) about 50 mg/mL to about 1000 mg/mL of propylene glycol and
(ii) about 1 mg/mL to about 25 mg/mL of triacetin.

[020] In yet another embodiment, the lenalidomide liquid oral solution of the present invention contains a cyclodextrin derivatives selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD). The most preferably used cyclodextrin derivative is sulfobutyl ether ß-cyclodextrin (SBEßCD). In one embodiment the liquid oral solution of the present invention contains of about 50 mg/mL to about 500 mg/mL of sulfobutyl ether ß-cyclodextrin (SBEßCD).

[021] In one embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate; and
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD).

[022] In another embodiment, the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) an organic solvent mixture of propylene glycol and triacetin; and
(c) sulfobutyl ether ß-cyclodextrin (SBEßCD).

[023] In a still further embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) about 50 mg/mL to about 500 mg/mL of sulfobutyl ether ß-cyclodextrin (SBEßCD); and
(c) an organic solvent mixture consisting of
(i) about 50 mg/mL to about 1000 mg/mL of propylene glycol and
(ii) about 1 mg/mL to about 25 mg/mL of triacetin.

[024] In one embodiment of the invention, the oral solution of lenalidomide of present invention comprises a preservative. As used herein, the term “preservative” is intended to mean a compound used to prevent the growth of microorganisms. Such compounds include, by way of example and without limitation, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, phenylmercuric acetate, thimerosal, metacresol, myristylgamma picolinium chloride, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, thymol, and methyl, ethyl, propyl, or butyl parabens. The most preferably used preservative in the present invention is benzalkonium chloride.

[025] In one embodiment of the invention, the oral solution of lenalidomide of present invention comprises an antioxidant. As used herein, the term “antioxidant” is intended to mean an agent which inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process. Such compounds include by way of example and without limitation, acetone, sodium bisulfate, ascorbic acid, ascorbyl palmitate, citric acid, butylated hydroxyanisole, butylated hydroxytoluene, hydrophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium citrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodium formaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite, EDTA (edetate), pentetate and others known to those of ordinary skill in the art. The most preferably used antioxidant in the present invention is ascorbic acid.

[026] In another embodiment the present invention provides a stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate;
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD);
(d) at least one preservative;
(e) at least one antioxidant and
(f) purified water.

[027] In one embodiment of the invention, the present invention provides the oral solution of lenalidomide, wherein the lenalidomide oral solution has a pH of about 2.0 to about 6.5. It is observed that the oral lenalidomide solution with the buffering agents having the pH of more than 6.5 has been degraded heavily (only 10% of lenalidomide is present, 90% of lenalidomide is degraded) when stored at 40°C for 4 days.

[028] In another embodiment of the invention the oral solution of lenalidomide of present invention comprises flavors. As used herein, the term “flavor” is intended to mean a compound used to impart a pleasant flavor and often odor to a pharmaceutical preparation. Exemplary flavoring agents or flavorants include synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may also include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Other useful flavors include vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. Flavors which have been found to be particularly useful include commercially available strawberry, orange, grape, cherry, vanilla, mint and citrus flavors and mixtures thereof. The amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors will be present in any amount as desired by those of ordinary skill in the art.

[029] In embodiments of the invention the oral solution of lenalidomide of present invention comprises pH adjusting agents selected from group consisting of sodium hydroxide and hydrochloric acid.

[030] In a further embodiment of the invention the oral solution of lenalidomide of present invention shall further comprise other pharmaceutically acceptable excipients selected from the group consisting of sweeteners and buffering agents.

[031] As used herein, the term “sweetener” is intended to mean a compound used to impart sweetness to a preparation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, xylitol, cyclodextrin, neotame, fructose, high fructose corn syrup, maltodextrin, sucralose, sucrose, other materials known to one of ordinary skill in the art, and combinations thereof.

[032] As used herein, the term “buffering agent” is intended to mean a compound used to resist change in pH upon dilution or addition of acid or alkali. Such compounds include, by way of example and without limitation, acetic acid, sodium acetate, adipic acid, benzoic acid, sodium benzoate, citric acid, maleic acid, monobasic sodium phosphate, dibasic sodium phosphate, lactic acid, tartaric acid, glycine, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, sodium bicarbonate, sodium tartrate and sodium citrate anhydrous and dihydrate and others known to those of ordinary skill in the art.

[033] In another embodiment of the invention, the oral solution of lenalidomide of the present invention is used to treat various cancers which includes multiple myeloma (MM), multiple myeloma (MM) following autologous hematopoietic stem cell transplantation (auto-HSCT), myelodysplastic syndrome (MDS), mantle cell lymphoma (MCL), follicular lymphoma (FL) and marginal zone lymphoma (MZL).

[034] In further embodiment of the invention, the oral solutions of lenalidomide of the present in packed in glass or plastic bottles, with or without graduations.

[035] The following example is provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the example below. The example should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

[036] EXAMPLE 1: SOLUBILITY AND STABILITY STUDIES OF LENALIDOMIDE IN VARIOUS ORGANIC SOLVENTS OR MIXTURES THEREOF.

[037] In this example, a comparison is made of several organic solvents and their mixtures as to their capacity of dissolving lenalidomide and stability of lenalidomide on storage. The solutions are made by first mixing the solvents and then adding lenalidomide. Each time the maximum quantity of lenalidomide is determined at which the solution is still stable and the stability results are recorded at initial point and on storage at 60°C for 4 days. The results of solubility and stability of lenalidomide are outlined in the following Table – 1 and Table – 2 respectively.
Table – 1 (Solubility Studies)

Lenalidomide Component Solvent mixtures Solubility
(mg/mL) Suitable for solution preparation
100 mg Lenalidomide 100 g of medium chain triglycerides 0.1 mg/mL No
100 mg Lenalidomide 100 g of glycerin 1 mg/mL Just suitable
100 mg Lenalidomide 100 g of polyethylene glycol 400 1 mg/mL Just suitable
100 mg Lenalidomide 100 g of propylene glycol 1 mg/mL Just Suitable
Lenalidomide Triacetin 2 mg/mL + propylene glycol- q.s to 1 mL 2.5 mg/mL Yes Suitable
Lenalidomide Triacetin 10 mg/mL +
propylene glycol q.s to 1 mL 3.5 mg/mL Well suitable
Lenalidomide Triacetin 10 mg/mL +
0.7 g/mL propylene glycol+
polyethylene glycol 400 q.s to 1.0 mL 3.5 mg/mL Well suitable
Lenalidomide Triacetin 10 mg/mL +
0.7 g/mL propylene glycol+
Glycerin q.s to 1 mL 3.5 mg/mL Well suitable

Table – 2 (Stability Studies)

Lenalidomide Component Solvent mixtures Stability Condition Impurities
Single Max Total
100 mg Lenalidomide 100 g of medium chain triglycerides Initial 0.39 0.56
60°C – 4 days 2.90 6.08
100 mg Lenalidomide 100 g of glycerin Initial 9.49 12.99
60°C – 4 days 48.11 78.88
100 mg Lenalidomide 100 g of polyethylene glycol 400 Initial 0.56 2.97
60°C – 4 days 3.48 27.17
100 mg Lenalidomide 100 g of propylene glycol Initial 0.28 0.62
60°C – 4 days 5.68 11.95
Lenalidomide Triacetin 2 mg/mL + propylene glycol- q.s to 1 mL Initial BQL 0.14
60°C – 4 days 1.3 2.9
Lenalidomide Triacetin 10 mg/mL +
propylene glycol q.s to 1 mL Initial BQL 0.2
60°C – 4 days 0.6 1.9
Lenalidomide Triacetin 10 mg/mL +
0.7 g/mL propylene glycol+
polyethylene glycol 400 q.s to 1.0 mL Initial 1.1 2.1
60°C – 4 days 17.0 39.9
Lenalidomide Triacetin 10 mg/mL +
0.7 g/mL propylene glycol+
Glycerin q.s to 1 mL Initial 0.09 0.3
60°C – 4 days 3.40 10.0
BQL: Below quantification limit.

[038] EXAMPLE 2: SOLUBILITY AND STABILITY STUDIES OF LENALIDOMIDE WITH CYCLODEXTRIN DERIVATIVES AND VARIOUS SOLVENTS OR MIXTURES THEREOF.

[039] In this example, a comparison is made of with combination of cyclodextrin derivatives and several solvents and their mixtures as to their capacity of dissolving lenalidomide and stability of lenalidomide on storage. The solutions are made by first mixing the solvents, cyclodextrin derivatives and then adding lenalidomide. Each time the maximum quantity of lenalidomide is determined at which the solution is still stable and the stability results are recorded on storage at 60°C for 4 days. The results of solubility and stability of lenalidomide are outlined in the following Table – 3 and Table – 4 respectively.
Table – 3 (Solubility Studies)

Lenalidomide Component Combination of cyclodextrin derivatives and solvent mixtures Solubility
(mg/mL) Suitable for solution preparation
Lenalidomide Sulfobutyl ether ß-cyclodextrin 250 mg/mL +
Purified water – q.s to 1 mL 3 mg/mL Well suitable
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Purified water – q.s to 1 mL 3 mg/mL Well suitable
Lenalidomide Hydroxy propyl ß- cyclodextrin 350 mg/mL+
Purified water – q.s to 1 mL 3 mg/mL Well suitable
Lenalidomide Hydroxy propyl ß- cyclodextrin 500 mg/mL+
Purified water – q.s to 1 mL 5 mg/mL Well suitable
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Phosphate buffer (pH 7.5) – q.s to 1 mL 3 mg/mL Well suitable
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Tris HCl buffer (pH 8.6) – q.s to 1 mL 3 mg/mL Well suitable
Lenalidomide Sulfobutyl ether ß-cyclodextrin 300 mg/mL +
Purified water 200 mg/mL +
Triacetin 10 mg/mL +
Propylene glycol – q.s to 1 mL 5 mg/mL Well suitable

Table – 4 (Stability Studies)
Lenalidomide Component Combination of cyclodextrin derivatives and solvent mixtures Stability Condition Impurities
Single Max Total
Lenalidomide Sulfobutyl ether ß-cyclodextrin 250 mg/mL +
Purified water – q.s to 1 mL 60°C –
4 days 3.40 6.9
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Purified water – q.s to 1 mL 60°C –
4 days 3.1 4.5
Lenalidomide Hydroxy propyl ß- cyclodextrin 350 mg/mL+
Purified water – q.s to 1 mL 60°C –
4 days 5.6 11.4
Lenalidomide Hydroxy propyl ß- cyclodextrin 500 mg/mL+
Purified water – q.s to 1 mL 60°C –
4 days 4.9 9.5
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Phosphate buffer (pH 7.5) – q.s to 1 mL 60°C –
4 days 90% of the lenalidomide degraded. Only 10% drug present.
Lenalidomide Sulfobutyl ether ß-cyclodextrin 350 mg/mL +
Tris HCl buffer (pH 8.6) – q.s to 1 mL 60°C –
4 days 90% of the lenalidomide degraded. Only 10% drug present.
Lenalidomide Sulfobutyl ether ß-cyclodextrin 300 mg/mL +
Purified water 200 mg/mL +
Triacetin 10 mg/mL +
Propylene glycol – q.s to 1 mL 60°C –
4 days 1.6 4.7

[040] EXAMPLE 3: STABILITY OF LENALIDOMIDE SOLUTION WITH VARIOUS ANTIOXIDANTS.

[041] In this example, a comparison is made of with various antioxidants for the stability of lenalidomide oral solutions. The stability results are recorded at initial and on storage at 25°C for 1 month. The solubility and stability results are tabulated in Table – 5.

Table – 5
Type of Composition Composition of Lenalidomide oral Solution Solubility
(mg/mL) Stability Condition Impurities
Single Max Total
Composition without antioxidant Lenalidomide+
Purified water 200 mg/mL+
Triacetin 10 mg/mL+
Frozen peppermint 0.01 mg/mL+
Sulfobutyl ether ß-cyclodextrin 300 mg/mL+ Propylene glycol to 1 ml 5 mg/mL Initial BQL 0.13
25°C – 1 Month 0.79 2.00
Composition with Thioglycolic acid as antioxidant Lenalidomide+
Purified water 200 mg/mL+
Triacetin 10 mg/mL+
Frozen peppermint 0.01 mg/mL+
Sulfobutyl ether ß-cyclodextrin 300 mg/mL+
Thioglycolic acid 3 mg/mL+
Propylene glycol q.s to 1 ml 5 mg/mL Initial 2.47 8.44
Composition with
L-ascorbic acid as antioxidant. Lenalidomide+
Purified water 200 mg/ml+
Triacetin 10 mg/mL+
Frozen peppermint 0.01 mg/mL+ Sulfobutyl ether ß-cyclodextrin 300 mg/mL+
Ascorbic acid 0.1 mg/mL +
Propylene glycol q.s to 1 ml 5 mg/mL 60°C –
4 days BQL 0.17
25°C – 1 Month 0.19 0.65
BQL: Below quantification limit.

[042] EXAMPLE 5: ORAL SOLUTION OF LENALIDOMIDE

[043] COMPOSITION
S. No Ingredients Quantity mg/mL
1. Lenalidomide 5
2. Triacetin 10
3. Purified water 200
4. Sulfobutyl ether ß-cyclodextrin (SBEßCD) 300
5. L-Ascorbic acid 0.5
6. Benzalkonium chloride 0.2
7. Propylene glycol 600
8. Peppermint flavour 0.01
9. Propylene glycol q.s to 1mL

[044] Process for preparation:
1. Required quantity of purified water was added to the stainless-steel manufacturing vessel.
2. Required quantity of propylene glycol (600 mg/mL) was added to the contents of manufacturing vessel in step 1 and mixed till propylene glycol and water is miscible.
3. Required quantity of triacetin was added to the contents of step 2 and mixed till it is miscible.
4. Required quantity of Sulfobutyl ether ß-cyclodextrin was added to contents of step 3 and mixed till it gets completely dissolved.
5. Required quantity of benzalkonium chloride was added to contents of step 4 and mixed till it gets completely dissolved.
6. Required quantity of ascorbic acid was added to contents of step 5 and mixed till it gets completely dissolved.
7. Required quantity of lenalidomide was added to contents of step 6 and mixed till it gets completely dissolved.
8. Required quantity of peppermint flavor was added to contents of step 7 and mixed till it gets completely dissolved.
9. The volume was finally made up with required quantity of propylene glycol.

[045] EXAMPLE 6: STABILITY RESULTS OF ORAL SOLUTION COMPOSITION OF LENALIDOMIDE OF EXAMPLE– 5.

[046] The oral solution composition of lenalidomide of example – 5 are stored at 2 – 8°c, 25°c and 40°c and the results of stability are tabulated in Table – 6.
Table – 6
Parameters Initial 2-8°C 25°C 40°C
2 weeks 1
Month 2 weeks 1M 2
weeks 1
Month
Assay (%) 99.8 99.4 99.5 96.4
pH 4.33 4.34 4.27 4.21
Impurity B (%) ND ND ND ND 0.01 0.03 0.07
Impurity C (%) 0.08 0.08 0.08 0.10 0.09 0.10 0.09
Impurity D (%) ND ND ND ND ND ND ND
Single max impurity (%) BQL BQL BQL 0.04
0.10 0.15 0.43
Total impurities (%) 0.11 0.11 0.11 0.18 0.20 0.62 1.56
BQL: Below quantification limit.
ND: Not detected.
,CLAIMS:1. A stable pharmaceutical liquid solution for oral administration comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide and
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate.

2. A stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate; and
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD).

3. The stable pharmaceutical liquid oral solution as claimed in claim 1, wherein the solution further comprises at least one preservative.

4. The stable pharmaceutical liquid oral solution as claimed in claim 1, wherein the solution further comprises at least one antioxidant.

5. The stable pharmaceutical liquid oral solution as claimed in claim 1, wherein the solution further comprises water.

6. A stable pharmaceutical liquid oral solution comprising
(a) about 1 mg/mL to about 30 mg/mL of lenalidomide;
(b) at least one organic solvent selected from group consisting of ethanol, glycerin, polyethylene glycol, propylene glycol, triacetin and triethyl citrate;
(c) at least one cyclodextrin derivative selected from group consisting of hydroxy propyl ß-cyclodextrin (HPßCD) and sulfobutyl ether ß-cyclodextrin (SBEßCD);
(d) at least one preservative;
(e) at least one antioxidant and
(f) purified water.